Natural Killer (NK) cells are thought to play a role in the control of viral infection prior to the establishment of an MHC restricted CTL response. Recently, specific recognition of alloantigens by NK cells was reported. Most of the cells displaying NK activity belong to the CD3-CD4- CD8-CD16+CD56+ subset of peripheral blood lymphocytes. The aim of this study is to determine the degree of target cell specificity displayed by NK clones and to eventually define the mechanism of target cell recognition by NK cells. As a first step, it was established that NK clones from a normal individual were able to specifically recognize and kill normal cells from the same individual that had been infected in vitro with Human Herpes Virus 6 (HHV6). However, only about half of the clones (58/118) were able to kill human Herpes virus 6 (HHV6)-infected autologous PHA-blasts, while all of them lysed the NK-sensitive cell line K562. A group of clones from two individuals were further characterized for their ability to recognize autologous and allogeneic infected cells. The results shoed for the first time that specificity in target cell recognition by NK cells is controlled at several levels: first, at the level of the NK clone itself, and second, by genetically variable elements on the target cells. Because the cell surface level of class I MHC molecules was virtually unaffected by HHV6 infection, recognition by NK cells of these particular targets cannot be explained by the mere absence of class I molecules, as was proposed to explain the NK-mediated killing observed in other systems.